When a poorly soluble drug having a polar group in the molecule is orally administered, oral absorption may in some cases be reduced due to low solubility in the pH condition in the gastrointestinal tract. In particular, many of the compounds having an acidic group in the molecule lose solubility as the pH become lower and result in poor solubility. Thus, when such compounds are orally administered, they are not efficiently dissolved from the preparation in the stomach, or they soon precipitate even when they are once dissolved. The low oral absorption has been the problem.
A method of forming solid dispersions is known as a method for improving the oral absorption of a poorly soluble drug. However, solid dispersions are produced by supporting a refined poorly soluble drug in a substrate, thus the poorly soluble drug exists in an amorphous state in the solid dispersions, and the surface energy of the particles is high. Thus, the solid dispersions have poor physical stability (non-patent document 1). Moreover, in the case of solid dispersions, a disintegrator such as conventional croscarmellose calcium or low substituted hydroxypropyl cellulose alone cannot exhibit sufficient disintegration (patent document 1).
Accordingly, a method other than forming solid dispersions is expected to be developed as a method for improving the oral absorption of a poorly soluble drug.
Various studies have been conducted to find other methods to improve the solubility of a poorly soluble drug. For example, when the poorly soluble drug is a compound having an acidic group in the molecule, (1) a preparation having improved solubility by making the poorly soluble drug an salt (patent document 2) and (2) a preparation having improved solubility by creating an alkali environment in the vicinity of the poorly soluble drug by compounding an alkali agent (patent documents 3 to 5, non-patent document 2), and the like have been reported.
However, patent document 2 states that, even though the solubility to water with a pH of 7 is improved by making the poorly soluble drug a salt, precipitation of the drug may be triggered by the acidic pH condition of the stomach after oral administration.
The preparation described in patent document 3 is produced by adding from outside an alkali agent to a granulated substance containing a poorly soluble drug. Likewise, the preparation described in non-patent document 2 is produced by directly tablet-compressing a mixture comprising a poorly soluble drug and an alkali agent, thus an alkali environment needs to be created in the entire preparation, as compared to the case where an alkali environment is created only inside the granulated substance by compounding an alkaline agent exclusively into the inside of the granulated substance containing the poorly soluble drug. Thus, each of the preparations described in the documents stated above needs to compound a large amount of alkali agent to be a preparation of a drug with especially high poor solubility, and thus it is not an adequate preparation.
Moreover, the preparations described in patent documents 4 and 5 are produced by granulating a poorly soluble drug, an alkaline agent and a disintegrator in a lump, thus at the time of disintegration when the granulated substance itself disintegrates, there is a possibility that the alkaline agent disperses from the vicinity of the poorly soluble drug and the environment adequate for dissolving the poorly soluble drug may be lost.